This invention relates to methods for treatment of bronchial asthma and other bronchospastic and allergic diseases. More particularly it relates to a method of treating these diseases employing certain substituted xanthine compounds.
Bronchial asthma is characterized by bronchospasm caused by contraction of the bronchial smooth muscle, increased secretion of mucus from the bronchi, and edema of the respiratory mucosa. While the etiology of asthma is not completely known, it is believed to involve an allergic reaction. Allergic reactions occur in sensitized individuals who are exposed to the antigen to which they are sensitized. The antigen provokes the release in the body of certain chemicals (allergic mediators) which in turn produce the allergic symptoms. Allergic reactions can also produce effects in organs other than the bronchi, particularly the skin, eyes and nasal mucosa and include such diseases as allergic rhinitis and urticaria.
Acute asthmatic bronchospasm has been treated with drugs which relax bronchial smooth muscle. Sympathomimetic drugs such as epinephrine, isoproterenol, and terbutaline and xanthine drugs such as theophylline and its salts (aminophylline, etc.) have been used for this purpose. Drugs such as cromolyn sodium which inhibit the release of allergic mediators, have been used prophylactically to treat bronchial asthma. Corticosteriod drugs have also been used to treat bronchial asthma and other allergy diseases.
Many of the drugs used hitherto have shortcomings which make them less than ideal for treatment of asthma and other bronchospastic and allergic diseases. For example, epinephrine and isoproterenol relieve the symptoms of asthma for only a relatively short period of time and are ineffective orally. Theophylline has limited efficacy and produces cardiac and gastrointestinal side effects. Cromolyn sodium is only effective by inhalation or injection and is ineffective by oral administration. The corticosteriod drugs have serious side effects which limit their chronic use.
Substituted xanthines have been known for some time as bronchodilators, and theophylline (1,3-dimethylxanthine) has long been used in the treatment of bronchial asthma.
Prior attempts have been made to improve theophylline by substituting the xanthine nucleus with different groups in several positions in the molecule. A number of 1,3-dialkylxanthines and 1,3,8-trialkylxanthines have been shown to be bronchodilators in animal models. However, none of the substituted xanthine compounds hitherto synthesized have displaced theophylline and its salts as clinically useful bronochodilator and antiallergy agents.
Stoll (Stoll, J. H. et.al., U.S. Pat. No. 2,729,643, issued Jan. 3, 1956.) describes the formation of intermediate products which he defines by way of a generic structural formula. This formula appears to broadly cover the compounds of this invention but Stoll has no specific disclosure of 3-(2-methyl-1-butyl) substituted xanthines.
Stoll's specific compounds of the 1,3,8-trialkylxanthine type are limited to those which have the same alkyl groups in both 1- and 3- position. He does not disclose any 1,3,8-trialkylxanthines having a 1-methyl group combined with a group in the 3-position having 4 to 7 carbon atoms.
Certain compounds disclosed by LeRoy, et.al., J. Pharmacol. Exptl. Therap. 69, 45-51 (1940), Speer, et.al., J. Am. Chem. Soc. 75, 114-115 (1953), and Stoll may be construed as being structurally similar to the compounds of this invention but none of these references suggests a bronchodilating or anti-allergen use.
Armitage, (Armitage, A. K., et.al., Brit. J. Pharmacol., 17, 196-207 (1961).), who deals with certain di- and tri-alkyl xanthines, alleges uses relating to bronchodilation, but does not show a 2-methyl-1-butyl grouping in the 3-position. Thus, while a similar use is involved, the compounds of this invention and their improved properties are not suggested by these prior art compounds.
Goodsell, (Goodsell, E. B., et.al., J. Med Chem. 1971, 14 (12) 1202-1205.) who deals with tri-alkyl xanthines, discusses the 3', 5'-cyclic adenosine monophosphate phosphodiesterase inhibition by certain 1,3-dimethyl-8-alkylxanthines and also reports some pharmacological data for these compounds. However, Goodsell did not test these compounds for bronchodilation or antillergy properties either in vitro or in vivo. Furthermore, no experiments were done to test the duration of activity of these compounds. Hence, Goodsell teaches nothing regarding the long-acting bronchodilation and antiallergy properties of 8-alkylxanthines.
Beavo (Beavo, J. A., et.al., Mol. Pharmacol. 6 , 597-603) in a study of adenonine-3', 5'-monophosphate phosphodiesterase activity of substituted xanthines discloses a few compounds having an 8-alkyl group. His in vitro data do not teach anything about duration of pharmacological activity in vivo.
A class of substituted xanthine compounds has now been found which are very effective bronchodilator and antiallergy agents with rapid onset and prolonged duration of action. These compounds are effective, rapid-acting bronchodilators by all routes of administration and accordingly can be used to abort an acute bronchospastic attack. In addition, they are orally effective, long-acting antiallergy compounds, by suppressing the release of allergic mediators. Hence, these compounds may be used prophylactically to treat bronchial asthma, and other bronchospastic and allergic diseases.